Naproxen Fails to Get FDA Heart Safety Nod

Members of two FDA advisory committees meeting jointly rejected a change in the label on naproxen to reflect a lower cardiovascular risk compared with other nonsteroidal anti-inflammatory drugs (NSAIDs).

Recent evidence convinced nine of the panelists that naproxen carries a lower risk versus others drugs in the class, but failed to sway 16 others.

Those voting "No" on the question indicated that the current evidence on naproxen's safety -- much of which was indirect, coming from studies in which it served as a comparator to a coxib drug -- did not meet the standards necessary to support label statements.

On the other hand, several panelists on the "yes" side said they planned to change their own prescribing habits and, in some cases, their personal medications.

Brendan Everett, MD, MPH, of Brigham and Women's Hospital in Boston, said he would probably stop prescribing ibuprofen or celecoxib (Celebrex) for patients with cardiovascular disease. "There's enough clinical evidence to affect the way I practice on a day-to-day basis," he said.

The panel -- comprising members of FDA's arthritis and risk management committees -- split more closely on a question about label information on the duration of NSAID treatment that raises cardiovascular safety risks.

Currently, labels for these drugs say that short-term treatment is relatively safe; however, some recent studies have sown doubt. A total of 14 panel members said the current statement should be reconsidered, while 11 voted No. However, most of those in the latter camp indicated in post-vote discussion that they believed there is no completely safe dosing period.

The meeting represents the latest chapter in the story of the cardiovascular risks of NSAIDs that began when data started to emerge in the early 2000s raising questions about the COX-2 inhibitors, including rofecoxib (Vioxx) and celecoxib. In 2001, a study in the Journal of the American Medical Association linked those two drugs to elevated risks of thrombotic events compared with other NSAIDs.

FDA officials said they called the meeting to help them decide whether it should revisit decisions on labeling made nearly 10 years ago, in light of analyses published following the Vioxx brouhaha.

In 2006, Pfizer started the PRECISION trial to evaluate the relative safety of celecoxib versus naproxen or ibuprofen in patients with osteoarthritis or rheumatoid arthritis who had or were at high risk for cardiovascular disease. That trial is still ongoing. However, in light of the other studies suggesting greater safety with naproxen, the FDA is considering whether to stop it or at least require that participants undergo a new consent process.

One prominent cardiologist paid his own way to the meeting so that he could tell panel members why the these analyses were flawed.

Speaking during the meeting's public portion, Milton Packer, MD, of the University of Texas Southwestern Medical Center in Dallas, pointed out that the trials incorporated into these meta-analyses varied substantially in the patient populations and drug doses. He said their results were too weak to support a label change -- with which the majority of panel members agreed.

An FDA official at the meeting conceded that the agency had never approved a label claim that one drug was superior to another based solely on meta-analysis results.

With regard to PRECISION, one FDA reviewer in the briefing documents called for it to be halted because of the evidence of naproxen's superior safety.

"Randomization of subjects is no longer reasonable because of the recently delineated difference in cardiovascular risk among the treatments, and significant difficulties with interpretation of the results will compromise the trial's ability to meet its scientific objective," the staffer wrote. "If a clinical hold is not imposed, subjects should be re-consented so that they can be informed of the findings of the [Lancet] meta-analysis regarding the PRECISION study drugs, and can have the option of withdrawing."

However, most of the advisory committee members said that, because naproxen's safety advantage has not been proved, equipoise remains in PRECISION -- thus, there is no need to stop it or require that participants be re-consented.

Sanjay Kaul, MD, of the University of California Los Angeles, said the trial represents the best chance to find out whether naproxen does have a safety advantage, and that stopping it prematurely would do "disservice" to participants as well as the wider community.

"It could be clarified that the advice to use an NSAID for the shortest duration possible is not based on the absence of a cardiovascular risk during a short latency period, but is simply a prudent way to limit patient exposure," according to the FDA review documents.

Asked whether labeling for over-the-counter NSAIDs should be revised, panelists generally agreed that the current language on cardiovascular risks could be clarified, but with no consensus on specifics.

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.